Abstract
Bacteria of the Burkholderia cepacia complex (Bcc) can cause devastating pulmonary infections in cystic fibrosis (CF) patients, yet the precise mechanisms underlying inflammation, recurrent exacerbations and transition from chronic stages to acute infection and septicemia are not known. Bcc bacteria are generally believed to have a predominant extracellular biofilm life style in infected CF lungs, similar to Pseudomonas aeruginosa, but this has been challenged by clinical observations which show Bcc bacteria predominantly in macrophages. More recently, Bcc bacteria have emerged in nosocomial infections of patients hospitalized for reasons unrelated to CF. Research has abundantly shown that Bcc bacteria can survive and replicate in mammalian cells in vitro, yet the importance of an intracellular life style during infection in humans is unknown. Here we studied the contribution of innate immune cell types to fatal pro-inflammatory infection caused by B. cenocepacia using zebrafish larvae. In strong contrast to the usual protective role for macrophages against microbes, our results show that these phagocytes significantly worsen disease outcome. We provide new insight that macrophages are critical for multiplication of B. cenocepacia in the host and for development of a fatal, pro-inflammatory response that partially depends on Il1-signalling. In contrast, neutrophils did not significantly contribute to disease outcome. In subcutaneous infections that are dominated by neutrophil-driven phagocytosis, the absence of a functional NADPH oxidase complex resulted in a small but measurably higher increase in bacterial growth suggesting the oxidative burst helps limit bacterial multiplication; however, neutrophils were unable to clear the bacteria. We suggest that paradigm-changing approaches are needed for development of novel antimicrobials to efficiently disarm intracellular bacteria of this group of highly persistent, opportunistic pathogens.
Highlights
Bacteria belonging to the Burkholderia cepacia complex (Bcc) are ubiquitously found in the natural environment, the rhizosphere of plants, and were first identified as the cause of onion rot; they are important opportunistic pathogens of individuals with cystic fibrosis (CF) and chronic granulomatous disease (CGD) [1]
In this work we demonstrate that macrophages, but not neutrophils, critically contribute to the development of a rapidly fatal inflammatory infection caused by B. cenocepacia
In contrast to findings with other important human pathogens, including Mycobacterium and Salmonella, Bcc bacteria cannot replicate in zebrafish embryos depleted of macrophages, identifying macrophages as a critical site for bacterial replication in vivo
Summary
Bacteria belonging to the Burkholderia cepacia complex (Bcc) are ubiquitously found in the natural environment, the rhizosphere of plants, and were first identified as the cause of onion rot; they are important opportunistic pathogens of individuals with cystic fibrosis (CF) and chronic granulomatous disease (CGD) [1]. They have emerged in nosocomial infections of both immunocompromised and immunocompetent patients hospitalized for reasons unrelated to CF or CGD; these infections have been correlated with contaminated surfaces and central venous access [2,3,4], but not much is known about reasons for the pathological effects. No information is available about a role for neutrophils during nosocomial non-CF infections
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